The St. Louis County Insane Asylum was opened on April 23, 1869, reportedly admitting 129 patients on the opening day. Located on elevated ground on Arsenal Street, west of Kingshighway (about 4 miles southwest of downtown St. Louis), the hospital consisted of a 5-story central building, flanked on each side by 4-story wings with 5-story end pavilions. The 194-foot cast iron dome on the central building was visible across much of the city.

After the City of St. Louis separated from the County of St. Louis on October 22, 1876, the hospital was renamed the St. Louis Insane Asylum. It was renamed the City Sanitarium in 1910 and extensive additional wings were added in 1912. Though initially a custodial institution with room for about 250 patients, the City Sanitarium gradually became a hospital for the diagnosis and treatment of mental disorders, with a capacity for over 3,000 patients. In 1948, upon the receipt of one dollar, the City of St. Louis turned over control of the City Sanitarium to the State of Missouri, which renamed the institution the St. Louis (or Missouri) State Hospital.